PHYTOMEDICINE
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2025
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IF 8.3
Simin Tian,Guang Xin,Kun Zhang,Ao Wen,Xiuxiang Yu,Chengyang Ni,Yijiang Liu,Xiaojuan Li,Yu Cao,Wen Huang
Background Acute pancreatitis (AP) is an inflammatory disease of the pancreas marked by inflammation and acinar cell necrosis. Scutellariae Barbata (S. Barbata), a traditional Chinese herb for inflammation, has unclear efficacy for AP. Purpose This study examined the mechanism of eriodictyol, an active component of S. Barbata decoction, targeting pancreatic necrosis and inflammation for the first time. Study Design This study firstly evaluated the pharmacological effects of S. Barbata on AP. Transcriptomic analysis and pharmacological screening were performed to identify essential genes linked to pancreatic necrosis and specific bioactive compounds in S. Barbata. These candidates underwent thorough validation with multiple assays. Our findings strongly demonstrate effectiveness of S. Barbata in combating pancreatic necrosis and reveal the underlying mechanisms involved. Methods Animal experiments were conducted to assess the effects of S. Barbata on AP. Analysis of bulk and single-cell RNA-seq data identified PANoptosis. The protein-protein interaction network and Cytoscape were used to identify AP targets based on PANoptosis. The ConnectivityMap database was used to filter potential compounds from S. Barbatae based on specific targets. After quantifying eriodictyol, its binding to ZBP1 was confirmed through molecular docking, dynamic simulation, cellular thermal shift assay, mtDNA analysis, and ZBP1 overexpression in 266-6 cells. Experiments in vivo and in vitro assessed the effects of eriodictyol on AP. Results S. Barbata decoction reduced pancreatic inflammation and necrosis. Gene Set Enrichment Analysis of PANoptosis revealed that Zbp1, Nlpr3, Ripk1, Casp8, Gsdmd , and Mlkl are ZBP1-dependent targets for AP. Eriodictyol, the active compound in S. Barbata showed a strong affinity for ZBP1. Eriodictyol may enhance pancreatic conditions and reduce ZBP1-dependent protein expression, with minimal impact on mtDNA levels. Conclusion This study broadened the traditional use of S. Barbata suggested eriodictyol as a potential AP treatment candidate via ZBP1-dependent signaling.
研究领域:
药理学
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分子生物学
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中医药学
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DOI
PubMed
高影响因子
LIFE SCIENCES
·
2020
·
IF 3.647
Jing Yang,Yiwen Zhou,Jinsong Shi
Acute pancreatitis (AP) is a noninfectious inflammatory disease with high morbidity and mortality, which is characterized by severe inflammation and tissue necrosis. Cordycepin (CRD), derived from Cordyceps militaris , possesses anti-inflammatory effects and immunomodulation properties. Here, we investigated the protective effects of CRD on pancreatic injury and clarified potential mechanisms in AP model. There were established caerulein-induced AP and CRD pretreatment models in vivo and in vitro, as showed by serum enzymes, histopathological alterations and pro-inflammatory cytokines. Pretreatment with CRD notably downregulated the serum amylase and lipase levels and apparently reduced pancreatic histopathological alterations in AP mice. Meanwhile, the MPO staining confirmed that CRD pretreatment modulated the infiltration of neutrophils in AP mice. Furthermore, CRD markedly decreased the levels of pro-inflammatory factors (IL-6, IL-1β, and TNF-α) though inhibiting the activation of nuclear factor-κB (NF-κB) and NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in AP mice. In pancreatic acinar cancer cell 266-6, CRD pretreatment decreased cholecystokinin(CCK)-induced inflammatory response was consistent with those in vivo. Mechanistically, CRD was also revealed to activate activated protein kinase (AMPK) and attenuated inflammation both in vivo and in vitro. On the whole, this study indicated that CRD protects mice from pancreatic inflammatory process and damage by suppressed NF-κB and NLRP3 inflammasome activation via AMPK, which probably contributed to the potential therapy for AP.
研究领域:
药理学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2025
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IF 5.7
Liying Wang,Mengxiang Tian,Bingzhi Dong,Weiqi Li,Liang Shi,Yifan Tong,Wei Chen,Xin Yu,Hongxia Xu,Bo Shen,Hong Yu
Acute pancreatitis (AP) is a common abdominal inflammatory disease, characterized by pancreatic autodigestion, acinar cell necrosis, and systemic inflammation. Currently, there is a lack of specific drugs in the treatment of AP. Traditional Chinese medicine (TCM) is an effective approach in the prevention and treatment of AP, with rheum being one of the key components in commonly used TCM formulas for treating AP. We screened emodin as the core active ingredient of rheum and developed a heparin-modified emodin carrier, EMO@ZIF-8/Heparin (HEZ), which specifically delivers emodin to the inflamed pancreatic tissue via CD44-targeted macrophage activation. The HEZ exhibited higher macrophage uptake efficiency in the inflammatory microenvironment, restored the mitochondrial membrane potential, alleviated oxidative stress, and effectively reduced the levels of cytokines in the AP cell model. Moreover, the formulation exhibited targeted enrichment and retention in the pancreas under AP conditions, blocking the systemic inflammatory amplification cascade, reducing approximately 50% of pathological damage in both pancreatic and lung tissues, decreasing the proportion of apoptotic pancreatic cells, and increasing the 15-day survival rate of AP mice from 15% to around 50%. Mechanistically, the formulation restored impaired macrophage mitochondrial function to a healthy state by inhibiting the JNK pathway. In summary, the multifunctional HEZ provides an upstream therapeutic strategy by targeting macrophages in AP, offering a novel and effective approach to potentially enhance AP treatment in the future.
研究领域:
药理学
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免疫学
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生物材料
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中医学
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DOI
PubMed
高影响因子
DIGESTIVE DISEASES AND SCIENCES
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2025
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IF 2.5
Gao Tao,Zhang Huaisheng,Xu Yuan,He Guosong,Ma Huicong,Zheng Chuanming,Li Lei,Cheng Feng,Dou Hehe,Zhang Fulong,Zhao Heng,Qiu Zhaolei
Background Severe Acute Pancreatitis (SAP) is associated with significant intestinal injury and inflammation. Hypoxia-Inducible Factor-1α (HIF-1α) and NLRP3 inflammasome have been implicated in this process, but their specific roles remain unclear. Objective This study aims to elucidate the roles of HIF-1α and NLRP3 in the pathogenesis of SAP and their effects on intestinal injury, barrier function, and inflammatory responses. Methods A SAP rat model was established, and histological changes were assessed via HE staining. Western blot was used to analyze HIF-1α and NLRP3 expression in intestinal mucosa. The effects of HIF-1α modulation were examined using the activator DMOG and inhibitor BAY87-2243. Immunohistochemistry, ELISA, and TUNEL staining were used to evaluate intestinal barrier function, permeability markers, and apoptosis. Results HIF-1α and NLRP3 expression significantly increased in SAP rats, peaking at 72 h. HIF-1α activation aggravated intestinal injury and barrier dysfunction, decreasing tight junction protein levels and increasing epithelial apoptosis. Enhanced intestinal permeability and elevated pro-inflammatory cytokines were also observed. Furthermore, HIF-1α activation promoted NLRP3 inflammasome assembly, resulting in increased caspase-1 and IL-1β expression. Conclusion HIF-1α exacerbates intestinal injury and inflammation in SAP, likely through NLRP3 inflammasome activation. Targeting HIF-1α may offer a potential therapeutic approach for SAP-induced damage and inflammation.
研究领域:
医学
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分子生物学
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DOI
PubMed
高影响因子
GENES AND IMMUNITY
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2025
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IF 4.5
Lin Shizhao,Liang Feihong,Chen Changgan,Lin Jiajing,Wu Yuwei,Hou Zelin,Huang Heguang,Fang Haizong,Pan Yu
Severe acute pancreatitis (SAP) poses significant challenges due to its complex pathophysiology, which includes inflammatory-immune responses that cause considerable damage to both the pancreas and other tissues. In this study, we explored the role of Annexin A1 (Anxa1), a glucocorticoid-regulated protein recognized for its anti-inflammatory properties, in regulating inflammation during acute pancreatitis. Using flow cytometry, single-cell RNA sequencing, and gene expression analysis, we examined how Anxa1 expression is regulated in myeloid cells throughout acute pancreatitis, employing various animal models to evaluate the consequences of modulating Anxa1 on injuries induced by SAP. Our findings revealed dynamic regulation of Anxa1 expression in myeloid cells, with mice lacking Anxa1 exhibiting worsened pancreatic injury and heightened systemic inflammation, resulting in significant damage to extra-pancreatic organs such as the lungs, liver, and kidneys. In contrast, treatment with Ac2-26, a synthetic peptide derived from Anxa1, effectively mitigated both pancreatic and extra-pancreatic inflammation and tissue damage. Overall, this study highlights the critical role of Anxa1 in modulating inflammatory responses during acute pancreatitis. Targeting Anxa1 presents a promising therapeutic strategy to mitigate pancreatic injury and prevent systemic complications associated with severe acute pancreatitis.
研究领域:
医学
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免疫学
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病理学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2022
·Vol. 23
·期 3
·1252
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IF 6.208
Jing Yang,Xujiao Tang,Xue Ke,Yutong Dai,Jinsong Shi
Triptolide (TP), the main active ingredient ofTripterygium wilfordii Hook.f., displays potent anti-inflammatory, antioxidant, and antiproliferative activities. In the present study, the effect of TP on acute pancreatitis and the underlying mechanisms of the disease were investigated using a caerulein-induced animal model of acute pancreatitis (AP) and an in vitro cell model. In vivo, pretreatment with TP notably ameliorated pancreatic damage, shown as the improvement in serum amylase and lipase levels and pancreatic morphology. Meanwhile, TP modulated the infiltration of neutrophils and macrophages (Ly6G staining and CD68 staining) and decreased the levels of proinflammatory factors (TNF-α and IL-6) through inhibiting the transactivation of nuclear factor-κB (NF-κB) in caerulein-treated mice. Furthermore, TP reverted changes in oxidative stress markers, including pancreatic glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), in acute pancreatitis mice. Additionally, TP pretreatment inhibited intracellular reactive oxygen species (ROS) levels via upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes expression (HO-1, SOD1, GPx1 and NQO1) in vitro. Taken together, our data suggest that TP exert protection against pancreatic inflammation and tissue damage by inhibiting NF-κB transactivation, modulating immune cell responses and activating the Nrf2-mediated antioxidative system, thereby alleviating acute pancreatitis.Keywords:acute pancreatitis;triptolide;inflammatory responses;oxidative stress
研究领域:
药理学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2023
·Vol. 24
·期 14
·11554
·
IF 5.6
Chehao Lee,Guang Xin,Fan Li,Chengyu Wan,Xiuxian Yu,Lijuan Feng,Ao Wen,Yu Cao,Wen Huang
Ninjurin 1 (NINJ1) is a double-transmembrane cell-surface protein that might mediate plasma membrane rupture (PMR) and the diffusion of inflammatory factors. PMR is a characteristic of acinar cell injury in severe acute pancreatitis (SAP). However, the involvement of NINJ1 in mediating the PMR of acinar cells in SAP is currently unclear. Our study has shown that NINJ1 is expressed in acinar cells, and the expression is significantly upregulated in sodium-taurocholate-induced SAP. The knockout of NINJ1 delays PMR in acinar cells and alleviates SAP. Moreover, we observed that NINJ1 expression is mediated by Ca2+concentration in acinar cells. Importantly, we found that Ca2+overload drives mitochondrial stress to upregulate the P53/NINJ1 pathway, inducing PMR in acinar cells, and amlodipine, a Ca2+channel inhibitor, can reduce the occurrence of PMR by decreasing the concentration of Ca2+. Our results demonstrate the mechanism by which NINJ1 induces PMR in SAP acinar cells and provide a potential new target for treatment of SAP.Keywords:nerve-injury-induced protein 1;plasma membrane rupture;severe acute pancreatitis
研究领域:
胃肠病学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2025
·Vol. 39
·期 14
·e70867
·
IF 4.2
Xiaolin Dou,Zhongcheng Zhu,Qizhen Chen,Yebin Lu
Acute lung injury (ALI) is closely associated with high mortality in severe acute pancreatitis (SAP). Nr4a3 is a nuclear receptor with proinflammatory effects. The role of Nr4a3 in SAP-associated ALI is unclear. Caerulein (CRE)-induced AP mice represented significant pancreatic and lung pathological injury, with high Nr4a3 expression in lung tissues. Nr4a3 expression in lung tissues of AP mice inhibited CD31 expression, suggesting lung microvascular injury. In vitro and in vivo experiments were performed to investigate the effect of Nr4a3 inhibition in mitigating SAP-associated ALI. Nr4a3 downregulation reduced permeability, increased trans-endothelial electrical resistance (TEER) and VE-cadherin expression in TNF-α-induced human pulmonary microvascular endothelial cells (hPMVECs), suggesting recovered endothelial barrier function. Nr4a3 knockdown attenuated lung injury in AP mice, as reflected by restored lung edema and endothelial barrier function. Reduced inflammatory cell counts and mediators indicated that Nr4a3 knockdown mitigated lung inflammation in AP mice. The up-regulation of Nr4a3 in TNF-α-induced hPMVECs was further elevated after Sirt1 (a deacetylase) inhibition. Mechanistically, Sirt1 deficiency increased the enrichment of CREB at the Nr4a3 promoter through acetylating H3K27, thereby promoting Nr4a3 expression. Rescue experiments in vivo demonstrated that Nr4a3 knockdown attenuated lung injury aggravated by Sirt1 inhibition. These results suggested that Sirt1 might prevent CREB enrichment by inhibiting histone acetylation in the Nr4a3 promoter, thereby suppressing Nr4a3 expression and ultimately attenuating ALI. Graphical Mechanism diagram of Nr4a3 inhibition alleviating SAP-associated ALI. The high expression of Nr4a3 promotes inflammatory responses, increases the permeability of endothelial cells, and thus exacerbates SAP-induced ALI. Sirt1 regulates histone deacetylation in the promoter of Nr4a3, thereby affecting CREB recruitment and influencing Nr4a3 transcription. Sirt1-mediated transcriptional inhibition of Nr4a3 alleviates SAP-associated ALI. A few materials used in this figure were from Bioicons ( https://bioicons.com/ ) and these materials were all free.
研究领域:
分子生物学
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免疫学
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病理学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-10
·
IF 3.9
Hu Jian-Xiong,Chen Ying-Kai,Chen Shi-Jun,Lin Yan-Ya,Chen Jun-Nian,Xie Ying,Zhao Cheng-Fei,Chen Cun-Rong
To study the mechanism of calcitonin gene related peptide(CGRP) protecting acute pancreatitis based on metabolomics. 24 adult male rats were randomly divided into control group (Con), acute pancreatitis model group (AP), CGRP treatment group (CGRP + AP, abbreviated as CGRP) and CGRP antagonist(CGRP(8–37)) pretreatment group (preCGRP(8–37) + AP, abbreviated as CGRP37), with 6 rats in each group. After different interventions, pancreases of rats in each group were collected for pathological analysis, and serum was collected for metabolomics analysis. Pathological examination of the pancreas suggested that the inflammation of pancreatitis in AP group was significant, the inflammation of pancreatitis in CGRP group was significantly reduced, and the pancreatitis in CGRP37 group was aggravated. Metabolomics of rat serum suggested that the differences in metabolites in each group were mainly related to amino acid metabolism, coenzyme/vitamin metabolism, carbohydrate metabolism, lipid metabolism, digestive system and other metabolic pathways. According to the trend of metabolite changes, we found 6 differential metabolites that were significantly correlated with CGRP intervention, including L-Valine, 5-Aminopentanoic acid, 4-oxo-L-proline, L-glutamine, L-proline, and Ornithine, all of which were related to amino acid metabolism. CGRP can effectively protect acute pancreatitis, possibly by regulating amino acid metabolism to alleviate acute pancreatitis.
研究领域:
医学
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药理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Hongtao Duan,Rui Zhang,Aiminuer Asikaer,Liang Pan,Shui Wang,Kuilong Huang,Deshuai Lou,Yuanqiang Wang,Zhihua Lin,Yan Shen
Background & Aims: Acute pancreatitis (AP) is a life-threatening condition, and hypertriglyceridemia (HTG) is recognized as a factor exacerbating AP and impeding pancreatic regeneration. Nicotinamide mononucleotide (NMN), a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD + ), is extensively utilized to restore NAD + levels. However, the impact of NMN on HTG-AP has not been previously addressed, which prompted our investigation into its effects and underlying mechanisms in this study. Methods & Results: Here, through bioinformatics analysis and in vivo experiments, we identified abnormalities in the thioredoxin system. In vitro studies revealed that NMN rescued oleic acid (OA)- and palmitic acid (PA)-induced mitochondrial dysfunction and cellular injury in pancreatic acinar cells by suppressing thioredoxin-interacting protein (TXNIP) through NAD + /sirtuin 1 (SIRT1) signaling. Repeated administration of NMN significantly ameliorated P407 and caerulein (CER)-induced pancreatic injury and dysfunction in mice. Consistently, NMN exhibited the potential to reduce inflammatory responses, lower serum lipid levels, and mitigate the accumulation of reactive oxygen species (ROS). More importantly, sustained NMN treatment inhibited the NOTCH pathway and promoted M2-type macrophage dominance during the pancreatic repair phase, influencing early or late macrophage polarization, which significantly enhanced inflammation resolution. As expected, in vitro models using mouse bone marrow-derived macrophage (BMDM), RAW 264.7, and THP-1 cells confirmed that NMN influences macrophage phenotype through the NOTCH pathway. Conclusions: Therefore, NMN ameliorates pancreatic acinar cell injury via NAD + /SIRT1-mediated TXNIP suppression and may influence macrophage polarization by inhibiting NOTCH activation, offering a novel therapeutic strategy for the treatment and repair of HTG-AP.
研究领域:
医学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
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IF 4.8
Feng Chen,Minghua Su,Dong Han,Yifan Wang,Menglong Song
Methyltransferase-like 14 (METTL14) is implicated in the regulation of various inflammatory disorders. However, its function and molecular mechanism in severe acute pancreatitis (SAP) remains unrevealed. Here we reported an increase in METTL14 in the pancreas of SAP mice and cerulein-LPS-treated AR42J cells. METTL14 depletion reversed inflammatory response and ferroptosis by reducing the expression of SAT1 (spermidine/spermine N1-acetyltransferase 1) and ACSL4 (acyl-CoA synthetase long chain family member 4) in an m6A-dependent manner. IGF2BP2 (insulin like growth factor 2 mRNA binding protein 2) could recognize m6A-modified SAT1 and ACSL4 mRNA and enhance their stability. Moreover, METTL14 depletion ameliorated pancreatic injury, inflammation, and ferroptosis induced by SAP. METTL14 overexpression aggravated SAP by promoting ferroptosis in vivo. Therefore, these results demonstrated that METTL14-induced ferroptosis promoted the progression of SAP, and targeting METTL14 or ferroptosis could be a potential strategy for the prevention and treatment of SAP.
研究领域:
分子生物学
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炎症性疾病
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胃肠病学
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DOI
PubMed
高影响因子
Advanced Science
·
2025
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IF 14.1
Dan Wang,Shuya Wang,Jinjin Liu,Xiaojing Shi,Tingli Xiong,Ruishi Li,Wei Wei,Liandong Ji,Qiong Huang,Xuejun Gong,Kelong Ai
Acute pancreatitis (AP) is a primary contributor to hospitalization and in-hospital mortality worldwide. Targeted elimination of mitochondrial reactive oxygen species (mtROS) within pancreatic acinar cells (PACs) represents an ideal strategy for treating AP. However, existing drugs fail to overcome the physiological barriers of the pancreas to effectively reach PACs mitochondria due to the trade-off between conventional positively charged mitochondrial-targeting groups and their inability to penetrate the blood-pancreas barrier (BPB). Here, a tungsten-based heteropolyacid nano-antioxidant (mTWNDs) is introduced, co-modified with tannic acid (TA) and melanin, enabling site-specific clearance of mtROS in PACs, offering a highly effective treatment for AP. TA exhibits a strong affinity for proline-rich type III collagen and the mitochondrial outer membrane protein TOM20. This unique property allows mTWNDs to traverse the damaged BPB-exposing type III collagen to reach PACs and subsequently penetrate mitochondria for targeted mtROS elimination. In cerulein-induced AP mice, mTWNDs reversed AP at 1/50th the dose of N-acetylcysteine, suppressing PACs apoptosis and inflammation by blocking the stimulator of the interferon genes pathway activation in macrophage. This study establishes a mitochondrial-targeting antioxidant nanomedicine strategy for AP treatment.
研究领域:
医学
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纳米生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）